Brinzolamide and brimonidine for treating glaucoma

ABSTRACT

Methods and compositions for treating ocular conditions which find their etiology in compromised ocular blood flow with brinzolamide and brimonidine are disclosed.

This application is a continuation of U.S. Ser. No. 09/601,634, filedAug. 4, 2000, which derives priority from U.S. Ser. No. 09/928,987,filed Dec. 7, 1999, which claims priority from U.S. Pat. No. 60/112,750,filed Dec. 17, 1998.

This invention relates to the treatment of ocular diseases andconditions which find their etiology in compromised blood flow withnovel formulations of brinzolamide combined with brimonidine tartrateand the use of brinzolamide and brimonidine tartrate administeredseparately.

BACKGROUND OF THE INVENTION

Brinzolamide R-(+)-4ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2Hthieno[3,2,e]1,2 thiazene-6 sulfonamide-1,1 dioxide) is a carbonicanhydrase inhibitor disclosed in U.S. Pat. No. 5,378,703 and sold in atopical ophthalmic formulation (Azopt™) for lowering elevatedintra-ocular pressure (IOP) in patients with open-angle glaucoma orocular hypertension (OHT) (Alcon Laboratories, Inc., Fort Worth, Tex.).

Brimonidine tartrate ((5-bromo-6-2-imidzolidisnylideneamino) quinozolineL-tartrate) hereinafter “brimonidine” is a relatively selectivealpha-2-adrenergic agonist sold in a topical ophthalmic formulation(Alphagan™) for lowering elevated IOP in patients with openangle-glaucoma or ocular hyp e r tension (Allergan, Inc., Irvine,Calif.).

U.S. Pat. No. 3,890,319 discloses a class of compounds, includingbrimonidine, and their usefulness as antihypertensive agents. Certain compounds in the group have also been disclosed for treating physicalpain, anaesthetizing~ the central nervous system, to constrict bloodvessels, treat ischemia, decongest nasal passages, effect reduction ofone or more effects of an inflammatory disorder to increase retinalblood flow, and effect an altration in the rate of fluid transport inthe gastrointestinal tract, see U.S. Pat. No. 5,756,503 (Column 1, lines16-22). WO 97/01339 discloses the use of brimonidine to protect theoptic nerve and the retina from “noxious provocations,” see page 1,first paragraph.

Oral and i.v. administration of the CAIs, acetazolamide andmethazolamide, are known to increase both ocular and cerebral bloodflow. The dosages used to achieve meaningful results are relatively highand is due to a number of factors. These compounds have relatively lowaffinity for carbonic anhydrase in as measured by their Ki(disassociation constant) values and are only modest inhibitors of theenzyme as measured by their IC₅₀ values. They have low distributioncoefficients (octanol/water determined at pH 7.4) which is a measure oftheir lipophilicity. This low lipophilicity limits their ability tocross the blood retinal barrier. Finally, these compounds haverelatively short half-lives in whole blood. This relatively rapidelimination rate limits their ability to redistribute into the back ofthe eye and maintain adequate drug concentrations.

The preclinical and clinical data for the effect of topically dosedCAIs, in particular dorzolamide, on ocular blood flow are conflicting.Gruenwald, et al., Acta Ophthalmologica, 75:236-238 (1997) disclosedthat the use of dorzolamide has no effect on retinal vein blood flow innormal volunteers. Pillunat, et al., ARVO abstract, InvestigativeOphthalmology & Visual Sciences, Vol. 38, No. 4 (Mar. 15, 1997) showedthat topical dorzolamide did not alter optic nerve head blood flow inhealthy subjects. Shipman, et al., ARVO abstract, InvestigativeOphthalmology & Visual Sciences, Vol. 38, No. 4 (Mar. 15, 1997) foundthat dorzolamide did not alter the choroidal pressure flowrelationships. Koller, et al., ARVO abstract, InvestigativeOphthalmology & Visual Sciences, Vol. 38, No.4 (Mar. 15, 1997) showedthat topical dorzolamide did not change peripapillary blood flow. Astudy by Harris, et al., Acta Ophthalmologica, 74:4896 (1996) saiddorzolamide accelerated blood velocity in the retina and superficialoptic nerve head; and another study by Sugrue, et al. J. Ocular Pharm.,12 (3) 363-376 (1996) teaches that topical dorzolamide does not decreaseblood flow to the iris, ciliary processes, optic nerve, or retina inrabbits. Sponsel has presented a few studies which suggest that topicaldorzolamide has a positive effect on ocular blood flow. See ARVOabstracts, Investigative Ophthalmology & Visual Sciences, Vol. 37, No. 3(Feb. 15, 1996) and Vol. 38, No. 4 (Mar. 15, 1997). Healthy subjectstreated with dorzolamide exhibited accelerated artereovenous passagetime and an increase in optic nerve head velocity is described in WO96/37203. The publication further discloses the use of topical carbonicanhydrase inhibitors (CAIs) to increase retinal and optic nerve headblood velocity. Brinzolamide is not disclosed in any of thesereferences.

SUMMARY OF THE INVENTION

This invention is directed to the use of brinzolamide in combinationwith brimonidine to treat ocular diseases which have their etiology incompromised blood flow. These diseases include, but are not limited toglaucoma, occlusion conditions, diabetic retinopathy, and ocularneovascularization. These agents can be used either alone, in separatecompositions dosed within 5 to 10 min of each other, or together in asingle formulation.

DESCRIPTION OF PREFERRED EMBODIMENTS

Brimonidine is a potent and relatively selective α₂ agonist which hasbeen shown to effectively lower IOP in rabbits, monkeys and man. Upontopical ocular administration brimonidine causes vasoconstriction inscleral vessels. However, brimonidine does not appear to be avasoconstrictor in vessels in the back of the eye. While brimonidine isa relatively safe compound it has been shown to cause the side effectsof sedation and ocular hyperemia in an allergic like reaction in somepatients. These side effects are thought to be due to the relativelyhigh concentration of the drug administered topically. The sedation likeside effects are believed to be caused by the drug crossing the bloodbrain barrier and triggering the sedative effects. The mechanism bywhich brimonidine causes hyperemia is not well understood. It is likelythat the frequent instillation of relatively high drug concentrationscauses this side effect. Thus, lowering the overall dose of brimonidinewhile maintaining IOP control would be advantageous.

Combinations of brimonidine and brinzolamide represent a novel approachto producing potent and long lasting IOP lowering medications with fewerside-effects than observed when these are administered alone.

When two separate formulations of brinzolamide and brimonidine are used,the preferred administration sequence is brimonidine first andbrinzolamide second. In this case, brimonidine serves to constrictocular vessels and thereby reducing the flux of blood through theanterior portion of the eye. When brinzolamide is administered thereduced circulation in the eye should result in an increase in thebioavailability of the CAI. Overall this sequence is expected to resultin an increase in efficacy and duration of actions thereby reducing thefrequency of administration (i.e., from tid to bid). This would alsoresult in improved patient compliance.

When a single formulation of both agents is used the above advantagesare believed to apply. In addition, the novel compositions contemplatedhave relatively high viscosity and are expected to increase theretention of brimonidine in the cul-de-sac of the eye. The net impactallows for lowering the dose of brimonidine.

It is well established that blood flow is impaired in glaucoma; manyresearchers think there is a direct relationship between insufficientblood flow and neural damage. Thus, improving blood flow should decreasethe rate of damage. Clearly, any vascular occlusive event in the eyeleads to damage to the region with restricted blood flow; improvingblood flow in this region or in close-by tissue should minimize theseverity of this damage. The standard treatment for advanced diabeticretinopathy is retinal photocoagulation; this is thought to be effectiveby decreasing oxygen demand and thus decreasing the hypoxic signalreleased by the oxygen-starved tissue that leads to angiogenesis.Treatment that improves oxygen supply by improving ocular blood flow asproposed here would be preferable to this tissue destruction and shouldlead to the same benefit. Neovascularization of the retinal, choroidal,or iridial tissues arises by the action of angiogenic substance(s).Generally, these angiogenic substances are produced in ocular tissuewhich is suffering from hypoxia. Thus, it is believed that enhancingblood flow in these tissues will effectively prevent or stopneovascularization by alleviating the hypoxia.

Brinzolamide is a carbonic anhydrase inhibitor which has been found tobe effective in lowering the elevated intraocular pressure associatedwith ocular hypertension and glaucoma. The distribution coefficient,IC₅₀ and Ki values for brinzolamide are 6.56, 3.19 nM and 0.13 nMrespectively. Further studies discussed in the examples show that itpenetrates to the back of the eye following topical ocular delivery andis also effective in increasing blood flow in ocular tissues includingthe optic nerve head. Ocular diseases and conditions which find theiretiology in compromised blood flow can be treated with brinzolamide.These diseases and conditions include glaucoma including but not limitedto primary open angle glaucoma (POAG) and normal tension glaucoma alsoknown as low tension glaucoma or angle closure glaucoma, occlusionconditions, such as, branch vein occlusion and retinal artery or veinocclusion, diabetic retinopathy, and retinal or iris neovascularizationfrom any cause.

The distribution coefficients for other well known CAIs, methazolamide,acetazolamide and dorzolamide, are 0.64, 0.23, and 1.72 respectively.The IC₅₀ values (determined against human carbonic anhydrase II) are12.5 nM, 9.04 nM, and 3.74 nM respectively. The Ki values are 29.3 nM,33.8 nM, and 0.51 nM respectively. Dorzolamide is significantly morepotent than either acetazolamide or methazolamide as measured by Ki andIC₅₀ and is only slightly, ˜2x, more lipophilic as measured by itsdistribution coefficient. Thus, it is not expected to efficiently crossthe blood retinal barrier. None of these compounds have the requisitecharacteristics to efficiently improve ocular blood flow. Thus there isa need to identify superior agents to improve blood flow to the back ofthe eye.

The effect of brinzolamide on regional microvascular ocular blood flowof the cat and rabbit was evaluated using the laser Doppler flowmetry(LDF) and colored microsphere techniques as shown in Examples 1-3.Example 4 describes the tissue distribution of brinzolamide in the eyesof rabbits.

EXAMPLE 1

In a topical study, four cats were bilaterally treated twice a day withone drop of 1% brinzolamide and three cats with one drop of vehicle forone-week. Optic nerve head (ONH) blood flow was then measured by LDF inthe anesthetized, spontaneously breathing felines. The experiment wasrepeated after a one-week interval in the same cats to assess thereproducibility of the technique. Averaging the two blood flowmeasurements showed that ONH flow was increased by an average of 21.8%over that measured in the control group. In anesthetized, ventilatedcats, ONH blood flow was increased on average 16.5%±8% at 60 minutesfollowing a single topical dose. Intravenous brinzolamide produced a46±17% increase (p≦0.05) in ONH blood flow; ONH vascular resistance, ameasure of vascular tone in the ONH microcirculation, was reduced by35±8% (p≦0.05).

EXAMPLE 2

Intravenous administration of 0.5, 2.5, and 5 mg/kg of brinzolamide toanesthetized, ventilated New Zealand albino rabbits produced asignificant dose-related increase in total ocular blood which reflectedincreases in blood flow to the tissues of the eye measured by thecolored microsphere technique. Optic nerve head blood flow, measured byLDF, was also increased above baseline. Ocular vascular tone was reducedsince total ocular vascular resistance was decreased dose-dependently.In this experiment, it was also possible to compare blood flows of thenormal eye to the contralateral eye that was mildly hypofused due tounilateral carotid occlusion. Baseline blood flow was 657±36 μl/min inthe hypofused eye. Intravenous doses of brinzolamide produced similarincreases in total ocular blood flows of 29%, 68%, and 90% in normaleyes and increases of 21%, 64%, and 90% in hypofused eyes. The highestintravenous brinzolamide dose returned regional blood flows to thehypofused eye to baseline levels found in the normal eye. Percentagewise, the blood flow increase to the hypofused eye was greatest toiridial, ciliary, and choroidal tissues, respectively.

EXAMPLE 3

Topical ocular administration of brinzolamide 2% suspension, one droptwice daily, in a one-week multidose crossover study in nineacepromazine tranquilized Dutch-belted rabbits significantly increasedblood flow to the optic nerve head as measured by LDF. Baseline valuesfor optic nerve head (ONH) blood flow, blood pressure, heart rate,intraocular pressure (IOP), and acid-base balance were determined beforetreatment began and 7-14 days after completion of a treatment arm;baseline values for the measured variables did not significantly changeduring the experiment. Treatment measurements were made 90 minutes afterthe last dose on day eight. Optic nerve head blood flow and measuredsystemic variables were not changed by vehicle treatment. Minimaldisturbance of acid-base balance occurred in brinzolamide treatedanimals. IOP was decreased by 16.8±2.2% (p<0.05 versus vehicle; p<0.001versus baseline) and ONH blood flow was significantly increased by11.2±1.6% (mean±SEM; p<0.05) following topical brinzolamide. It isestablished that the vasculature of the ONH responds to increases inarterial O₂ or CO₂ tension by a reduction or an enhancement of ONH bloodflow, respectively. Since the blood flow increase in this experimentoccurred when arterial CO₂ tension was below and O₂ tension was abovebaseline levels, it can be suggested that brinzolamide has a localocular action on the optic nerve head vasculature independent of effectson blood gases.

EXAMPLE 4

The tissue distribution of brinzolamide was determined in New ZealandAlbino (NZW) and Dutch belted rabbits after a single topical ocular doseof 1% ¹⁴C-brinzolamide. In both species brinzolamide was found to slowlyredistribute into the retina. The T_(max) values in the retina were 20days and 36 days in the NZW and Dutch belted rabbits respectively. Thesedata demonstrate that brinzolamide is slowly delivered to the retinaover time and likely comes for the red blood cells. The C_(max) valueswere 0.330 and 0.338 ?g equivalents/g in the NZW and Dutch beltedrabbits respectively. These data show that the drug distribution is notinfluenced by the presence/absence of pigment and is not simply ameasure of red blood cell concentration.

Brinzolamide is preferably formulated as a topical ophthalmic suspensionwith a pH of about 4.5-7.8. It will normally be contained in theformulation at a concentration of0.1%-10% by weight, preferably0.25%-5.0% by weight. Thus, for topical presentation 1-3 drops of theseformulations would be delivered to the surface of the eye 1-4 times aday according to the routine discretion of a skilled clinician.

Brimonidine is preferably formulated as a topical ophthalmic solutionwith a pH of about 4.5-7.8. It will normally be contained in theformulation at a concentration of 0.01%-0.2% by weight, preferably0.1%-0.2% by weight. Thus, for topical presentation 1-3 drops of theseformulations would be delivered to the surface of the eye 1-4 times aday according to the routine discretion of a skilled clinician.

The combinations of brinzolamide and brimonidine are preferablyformulated as topical ophthalmic suspensions with a pH of about 6.5 to7.8. Brinzolamide will is normally be contained in the formulations atconcentrations of 1.0%-2.0% by weight, preferably 1.0% by weight.Brimonidine will normally be contained in the formulations atconcentrations of 0.01%-0.2% by weight, preferably 0.05%-0.2% by weight.For these formulations 1-2 drops would be delivered to the surface ofthe eye 1-3 times a day according to the routine discretion of a skilledclinician.

The following example is the preferred brinzolamide formulation for useaccording to the present invention.

EXAMPLE 5

Ingredient Percent w/v Brinzolamide 1.0 Mannitol 3.3 Carbopol 974P 0.4Tyloxapol 0.025 Disodium EDTA 0.01 Benzalkonium Chloride 0.01 + 5%excess Sodium Chloride 0.25 Sodium Hydroxide/Hydrochloric Acid pH 7.5Purified Water QS 100

EXAMPLE 6

Ingredient Percent w/v Brinzolamide 1.0 Brimonidine Tartrate 0.1Mannitol 3.3 Carbopol 974P 0.4 Tyloxapol 0.025 Disodium EDTA 0.01Benzalkonium Chloride 0.01 + 5% excess Sodium Chloride 0.25 SodiumHydroxide/Hydrochloric Acid pH 7.5 Purified Water QS 100

EXAMPLE 7

Ingredient Percent w/v Brinzolamide 1.0 Brimonidine Tartrate 0.05Mannitol 3.3 Carbopol 974P 0.4 Tyloxapol 0.025 Disodium EDTA 0.01Benzalkonium Chloride 0.01 + 5% excess Sodium Chloride 0.25 SodiumHydroxide/Hydrochloric Acid pH 6.5 Purified Water QS 100

EXAMPLE 8

Ingredient Percent w/v Brinzolamide 1.0 Brimonidine Tartrate 0.2Mannitol 3.3 Carbopol 974P 0.4 Tyloxapol 0.025 Disodium EDTA 0.01Benzalkonium Chloride 0.01 + 5% excess Sodium Chloride 0.25 SodiumHydroxide/Hydrochloric Acid pH 7.5 Purified Water QS 100

EXAMPLE 9

Ingredient Percent w/v Brinzolamide 1.0 Brimonidine Tartrate 0.02Mannitol 3.3 Carbopol 974P 0.4 Tyloxapol 0.025 Disodium EDTA 0.01Benzalkonium Chloride 0.01 + 5% excess Sodium Chloride 0.25 SodiumHydroxide/Hydrochloric Acid pH 6.5 Purified Water QS 100

EXAMPLE 10

Ingredient Percent w/v Brimonidine Tartrate 0.2 Polyvinyl Alcohol 1.4Benzalkonium Chloride 0.005% Citric Acid 0.042 Sodium Citrate 0.53Sodium Chloride 0.69 Sodium Hydroxide/Hydrochloric Acid QS pH 6.3-6.5Purified Water QS 100

We claim:
 1. A method for treating glaucoma which comprisesadministering a pharmaceutically effective amount of brinzolamide andbrimonidine.
 2. The method of claim 1 wherein the brinzolamide and thebrimonidine are dosed simultaneously in a single formulation.